7-substituted cephalosporanic acid and derivatives thereof

ABSTRACT

Disclosed herein are cephalosporanic acid and derivatives thereof which are substituted in the 7-position, processes for preparing such compounds and the utility thereof. The compounds of the invention have been found to be useful as antibacterial agents.

United States Patent Dolfini et al.

1 Feb. 18, 1975 7-SUBSTITUTED CEPHALOSPORANIC ACID AND DERIVATIVES THEREOF Inventors: Joseph Edward Dolfini, Princeton;

Ekkehard Biihme, Hightstown, both of NJ.

Assignee: E.R. Squibb & Sons, Inc., Princeton,

Filed: June 7, 1972 Appl. No.: 260,635

Related US. Application Data Continuation-impart of Ser. No. 119,034, Feb. 25, 1971, abandoned.

US. Cl. 260/243 C, 424/246 Int. Cl C07d 99/24 Field of Search 260/243 C Primary ExaminerNicholas S. Rizzo Attorney, Agent, or Firm-Lawrence S. Levinson; Merle J. Smith; Stephen B. Davis [57] ABSTRACT Disclosed herein are cephalosporanic acid and derivatives thereof which are substituted in the 7-position, processes for preparing such compounds and the utility thereof. The compounds of the invention have been found to be useful as antibacterial agents.

7 Claims, No Drawings 1 7-spasrrrur spcEPnALosPo mc cn) AND DERIVATIVES THEREOF This application is a continuation-in-part of application Ser. No. 119,034, filed Feb. 25, l97l, now abandoned.

SUMMARY OF INVENTION This invention relates to 7-substituted-7-aminocephalosporanic acid having the following Formula I:

a y I coon wherein R 'is a lkyl, aralkyl, alkylene alkyl, cycloalkyl or cycloalkylne and R is hydrogen, lower alkyl, aralkyl, substituted alkyl, substituted aralkyl or cation; Y is hydrogen, acetoxy, pyridinium, alkoxy, alkyl, mercapto, hyyzlroxy or alkylamino. These compounds have been found to be useful as antibacterial agents and as intermediates in the preparation of 7-acylamino-7- substituted cephalosporanic acids and pharmaceutically acceptable salts thereof.

DESCRIPTION OF INVENTION 1 chloride,

This reaction is conducted in the presence of a base, such as alkali metal hydroxide such as sodium hydroxide, triton-B, potassium t-butoxide, sodiummethoxide, or triphenylmethyl sodium, sodium hydride, etc.

Compounds of Formula Illthat may be utilized in the practice of the invention are methyl sulfate, ethyl sul fate, methyl p-toluenesulfonate, propyliodide, allylbenzylchloride, hexylchloride, 1,2- dichloropropene-Z, butylbromide, methyl iodide and so forth.

It is to be understood that the term lower alkyl and lower alkoxy 'in the formulae of the instant invention include straight and branched chain radicals of from I to about 8 carbons such as methyl, ethyl, propyl, iso-. propyl, butyl, isobutyl, t-butyl, amyl, methoxy, ethoxy, propoxy, isopropoxy, and the like. Further, it will be appreciated that certain of the compounds of this invention exist in different optically active forms. The various stereoisomeric forms as well as the racemic compounds are within the scope of this invention.

The term aryl, such as in aryl, aryloxy, arylthio, etc. is intended to include phenyl, aand B-naphthyl. In addition, the term aryl is intendedflto encompassmono and disubstituted-phenyl, or aand B-napthyl groups wherein said substituents are halogen, hydroxy, amino, nitro and alkyl. v

The term heterocyclyl, while intended to encompass the entire class, more specifically is intended to encompass the thiophene, isoxazole, oxadiazole, thiadiazole, pyridine, pyrazene, morpholine, quinoline, isoquinoline, tetrazole, furan, pyrrole and indole. The ring systems may be at various hydrogenated states, such as dihydrofuran and tetrahydrofuran. In addition, the

a di(lower alkyl)amine (e.g., diethylamine), a phenyl- R -cu-n- ---l o z c0 11. 4 II wherein R is phenyl, X-substituted phenyl, lower alkyl or aralkyl (e.g., benzyl or phenethyl), wherein X is ha]- I ogen (e.g., chloro, bromo), alkoxy, hydroxy, nitro,

amine, or lower alkyl; with a compound having the Formula lll:

lll wherein L is a leaving group such as halogen (e.g., chloro-, bromo-, and so forth), sulfonate, sulfate, me-

thylsulfonyloxy, p-toluenesulfonyloxy, and R and Y are as defined herein.

point of linkage may be at any of the possible ring positions and the ring systems may carry additional substituents such as alkyl, alkoxy, amino, nitro, halogen, etc.

Suitable compounds of Formula II include any Schiffs base of 7-ADCA or 7-ACA (or a protected form thereof). When using this process, the preferred.

Schiffs bases are those formed with aldehydes which do not interfere with the alkylation reaction; such as nitro, chloro, alkoxy or alkylbenzaldehydes. Thus, although any of the Schiffs bases of -APA disclosed in Patent application Ser. No. 84,946 nowabandoned can be used correspondingly with 7-ACA or 7-ADCA nuclei, the preferred are those of the formula: RCHO, wherein R is phenyl, p-methoxyphenyl, m nitrophenyl, halophenyl (e.g., p-chlorophenyl, m-fluorophenyl, and o-bromophenyl), (lower alkoxy)phenyl' (e.g., omethoxyphenyl), carbo(lower alkoxy)phenyl (e.g., p-carbomethoxyphenyl, o-carboethoxyphenyl, p-carbohexyloxyphenyl, and m-carbobutoxyphenyl), o-npropoxyphenyl, and p-n-hexyloxyphenyl), di(lower alkyl) aminophenyl [e.g., p-dimethylaminophenyl, odiethylaminophenyl, p-(N-n-butyl-N-methylamine)- phenyl, and m-di-n-pentylaminophenyl1, naphthyl. The reaction in forming compounds of Formula II is preferably conducted in an inert organic solvent for the Schiffs base reactant, suchas methylene chloride, benzene, dimethoxyethane, dioxane and chloroform.

Compounds of the Formula II can be used in either their salt form or in the form of an ester. Suitable salt forms include those with alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium). Suitable esters include those formed with lower alkanols (e.g., methanol, ethanol and tert.-butanol), cycloalkanols (e.g., cyclohexanol and cyclopentanol), carbocytrichloroethanol, 2-bromoethanol, p-nitrophenol, p-'

methoxyphenol, p-methoxybenzyl alcohol, p,p'-dimethoxybenzhydrol, Z-dimethylamino ethanol, p-' nitrobenzoylmethanol and p-methoxybenzoylmethanol.

The reaction of Compound ll with Compound Ill yields a compound of Formula IV:

which can then be converted to compounds of Formula I by hydrolysis in the presence of a mild aqueous acid, such as hydrochloric, sulfuric, formic, trifluoroacetic and acetic acid to yield the 7-substituted-7-aminocephalosporanic acid of Formula l.

As stated above compounds of Formulal are valuable intermediates in the formation of acylated com pounds having the- Formula V:

bon atoms and is alkyl, alkylthioalkyl or alkoxyalkoxyalkyl,

c. R CO- where R contains from two to seven carbon atoms and is alkenyl, alkylthioalkenyl, alkenylthioalkyl, alkoxyalkenyl or alkenyloxyalkyl,

d. R X,(CH ),,CO- where R and n are as defined above and X is oxygen or sulphur,

e. R (CH ),,S(CH ),,,CH CO- where R and n are as defined above and m is O or an integer from 1 to 4,

f. R CO- where R is as defined above,

g. R (CH ),,CO where R is carbocyclic or substituted carbocyclic (e.g., lower alkyl dihydrocyclohexyl, lower alkoxy dihydrocyclohexyl such as 2,4-dimethyl- 2,4dihydrocyclohexyl, and 2-propoxy-2,4- dihydrocyclohexyl), aryl, heterocyclyl, aryloxy, arylthio, and alkyloxy and n is an integer from 0, l to 4 where *R is as defined herein, R is alkyl, amino. ureido, carboxy, sulfonyl, phosphonyl, hydrogen, hydroxy, chloro, bromo, or iodo; p is an integer from 0, l to 3, and

where R R" and p are as defined above. Compounds of general Formula V are prepared from compounds of general Formula I.

The formation of compounds of general Formula V may, for example, be effected by one of the following methods:

a. Reaction of the compound of general Formula l with an acid chloride, or acid anhydride, active ester, acid azide, etc. in aqueous or organic solution.

b. Reaction of the compound of general Formula I with a mixed anhydride of an acid corresponding to the desired acyl group and another acid, the mixed anhydride being formed by reaction of the acid corresponding to the desired acyl group with an alkyl haloformate, if desired formed in situ; the reaction with the mixed anhydride preferably being conducted in solution in an anhydrous, inert solvent in the presence of an acid binding agent e.g., a tertiary amine.

c. Reaction of the compound of Formula I with the activated form ofa carboxylic acid formed by reaction with carbonyl-di-imidazole or dicyclohexylcarbodiimide or similar activating agent.

The compounds of this invention have a broad spectrum of antibiotic activity. They have antibacterial activity against microorganisms, such as Staphylococcus aureus, and Streptococcus pyrogenes. They may be used as antibacterial agents in a prophylactic manner, e.g., in cleaning or disinfecting compositions, or other wise to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to cephalothin, cephalexin, cephaloridine and other cephalosporins. For example, a compound of Formula I may be used in various animal species in an amount of about 0.1 to mg/kg daily.

The following examples illustrate the invention (all temperatures being in degrees centigrade, unless otherwise stated):

EXAMPLE 1 N-Benzylidene-7-Aminodesacetoxycephalosporanic Acid, t-octylamine Salt EXAMPLES 24 By following the procedure of Example 1 and substituting in place of the benzaldehyde. an equivalent amount of:

o-nitrobenzaldehyde,

m-chlorobenzaldehyde,

5 p-methoxybenzaldehyde, and p-methylbenzaldehyde,

the products obtained are:

N-o-nitrobenzylidene-7-aminodesacetoxycephalosporanic acid, t-octylamine salt; N-m-chlorobenzylidene-7-aminodesacetoxycephalosporanic acid, t-octylamine salt; N-p-methoxybenzylidene-7-aminodesacetoxycephalosporanic acid, t-octylamine salt; and N-p-methylbenzylidene-7-aminodesacetoxycephalosporanic acid, t-octylamine salt.

EXAMPLE 6 N-Benzylidene-7-Aminodesacetoxycephalosporanic Acid 73.8 Mmoles N-benzylidene-7- aminodesacetoxycephalosporanic acid, t-octylamine salt is added to 240 ml. methylene chloride cooled to 5C. (water bath). After dispersion 158.5 mmoles benzaldehyde are added, followed by the addition of an 8 ml. tetrahydrofuran solution containing 76.2 mmoles trifluoroacetic acid. During the course of this addition, the reaction mixture gradually clarifies to finally form a clear, slightly yellow solution. The reaction mixture is allowed to reach room temperature and concentrated to one-third its volume in vacuo at a temperature not exceeding 30C. On cooling the desired product crystallized out in 76 mole EXAMPLE 7 Benzyl ester of N-benzylidene-7-aminodesacetoxycephalosporanic acid Treatment of a 0.1 molar solution of N-benzylidene- 7-aminodesacetoxycephalosporanic acid with one equivalent of phenyl diazomethane in ether (Overberger and Anselme, J. ORG. CHEM., 28, 592 [1963]; ldem,.l. AM. CHEM. SOC., 86, 658 [1964] for 1 hour, followed by evaporation deposits the product.

EXAMPLE 8 Diphenylmethyl ester of N-benzylidene-7-aminodesacetoxycephalosporanic acid Substitution of one equivalent of diphenyldiazomethane for the solution of phenyl diazomethane in Example 7 gives the desired product.

EXAMPLE 9 Trichloroethyl ester of 7-benzaliminodesacetoxycephalosporanic acid The Schiff base of Example 1 (10.0 g) is dissolved in 150 ml. of dichloromethane containing pyridine (5.2 g). Trichloroethanol 9.84 g is added followed by 6.79 g dicyclohexylcarbodiimide and the mixture stirred for 2 hours at room temperature. Precipitation of dicyclohexylurea occurs quickly. After 2 hours the precipitate is filtered off. The filtrate is diluted with dichloromethane and washed twice with an equal volume of water, first at pH 3.5, then at pH 7.2. It is then washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and stripped to dryness in vacuo. Wt. of yellow oil 13.2 g.

The product is crystallized by dissolving it in ml. of ether and adding hexane to the warm solution until slightly turbid upon cooling.

EXAMPLE l0 p-Methoxybenzyl ester of 7-benzaliminodesacetoxycephalosporanic acid Substitution of 9.1 grams of p-methoxybenzyl alcohol for trichloroethanol in Example 9 leads to the desired product.

EXAMPLE 1 1 Methyl ester of 7-benzaliminodesacetoxycephalosporanic acid By treating a dioxane solution of the product of Example 6 with excess ethereal diazomethane, followed by evaporation of the solvent, the desired product is obtained. Trituration with hexane gives a powder.

EXAMPLE l2 7-Benzalimino-7-methyldesacetoxycephalosporanic acid methyl ester 12.5 Meq. 7-benzaliminodesacetoxycepthalosporanic acid methyl ester are dissolved in 2 ml. dry DME under nitrogen at 5C. Then a 20-fold excess methyl iodide is added along with 12.5 meq. sodium hydride. The reaction mixture turns yellow after a few minutes of stirring at that low temperature. After 3 hours, thin layer chromatography on Silica gel, showed no more starting material. The reaction mixture is diluted with chloroform, washed with water, dried over magnesium sulphate and evaporated in vacuo to give 4.8 grams of a brown oil. This was recrystallized from hexanedichloromethane to give 5.8 meq. 7-benzalimino-7-amethyldesacetoxycephalosporanic acid, methyl ester; chromatography of the mother liquors on Silica gel led to the isolation of the 7-B-methyl epimer.

EXAMPLE l3 7-Benzalimino-7-methyldesacetoxycephalosporanic acid, p-methoxybenzyl ester Substitution of 12.5 meq. of the p-methoxybenzyl ester of 7-benzaliminodesacetoxycephalosporanic acid in Example 12 for the methyl ester leads to the desired product.

EXAMPLE 14 7-Amino-7-methyl desacetoxycephalosporanic acid tion is rapidly stirred until hydrogen evolution is slowed.

or stops. Thin layer chromatography can be used to maintain disappearance of starting material and formation of the desired product. The reaction mixture is diluted with ml. water and the pH adjusted to 2.5 (at 0C). The result is filtered and extracted with 2 portions ether. The pH is readjusted to 4.5, and concentrated in vacuo if necessary, to precipitate the product.

b. 0.2 Mmole N-benzylidene-7-amino-7-methyldesacetoxycephalosporanic acid, p-methoxybenzyl ester are dissolved in 6.5 ml. benzene and 4.33 mmoles anisole and 7.6 mmoles TFA are added. The reaction is allowed to proceed at room temperature for 6 hours. The whole is concentrated under vacuum. The residue is washed with 20 percent etther/petroleum ether to leave acid in 65% yield. f

EXAMPLE 15 7-Benza1imino-7-methyldesacetoxycephalosporanic acid, benzyl ester Substitution of 12.5 meq. of the benzyl ester of 7- benzaliminodesacetoxycephalosporanic acid in Example 12 for the methyl ester leads to the desired product.

EXAMPLE 16 7-Benzaliminc-7-methyldesacetoxycephalosporanic acid, benzhydryl ester By substituting 12.5 meq. of the benzhydryl ester for the methyl ester of Example 12 the desired product is obtained.

EXAMPLE 17 7-Amino-7-methyldesacetoxycephalosporanic acid, methyl ester 6.2 Meq. 7-benzalimino-7-methyldesacetoxycephalosporanic acid, methyl ester are hydrolyzed in a 50:50 mixture of acetone and 0.1 N aqueous hydrochloric acid for minutes. The reaction mixture is then diluted with water and washed with chloroform. The acidic layer is then basified and extracted with chloroform. This latter chloroform layer is dried over magnesium sulphate and evaporated to dryness in vacuo. To give 5 meq. 7-amino-7- rnethyldesacetoxycephalosporanic acid, methyl ester.

EXAMPLE 18 7-Amino-7-methyldesacetoxycephalosporanic acid, p-methoxybenzyl ester Substituting 6.2 meq. of the product of Example 13, and following the procedure of Example 17 the desired product is obtained.

EXAMPLE l9 7-Amino-7-methyldesacetoxycephalosporanic acid, benzyl ester Substituting 6.2 meq. of the product of Example for the substrate of Example 17 and following the procedure therein, the desired product is obtained.

EXAMPLE 20 7-Amino-7-methy1desacetoxycephalosporanic acid, benzhydryl ester Substituting 6.2 meq. of the product of Example 16 for the substrate of Example 17 and following the procedure therein, the desired product is obtained.

EXAMPLE 21 7-Pheny1acetamido-7-methyldesacetoxycephalosporanic acid, methyl ester 7-methyl-7-aminodesacetoxycephalosporanic sium sulphate, and evaporated to dryness to give 1.7 meq. of 7-phenylacetamido-7-methyldesacetoxycephalosporanic acid, methyl ester as a clear oil which crystallizes on standing.

EXAMPLE 22 7-Phenylacetamido-7-methyldesacetoxycephalosporanic acid, p-methoxybenzyl ester Substituting 3.25 meq. of 7-amino-7- methyldesacetoxycephalosporanic acid. pmethoxybenzyl ester in Example 21 for 7-amino-7- methyldesacetoxycephalosporanic acid, methyl ester. and following the procedure therein, the desired product was obtained.

EXAMPLE 23 7-Phenylacetamido-7-methyldesacetoxycephalosporanic acid a. By hydrolysis; 1 mmole of the 7-phenylacetamid0 -7 --methyldesacetoxycephalosporanic acid, methyl ester in 10 ml. ethanol is treated with 1 ml. of 1N NaOH at room temperature for 6 hours with stirring; the alcohol is evaporated at reduced pressure. The residue is dissolved in water and pH adjusted to 7.5 if necessary. The aqueous solution is washed with ethyl acetate, filtered and acidified to pH 4 at 0C. to precipitate the product.

b. The product of Example 14 (obtained by using methyl iodide) as a solution with triethylamine in 1:1 water/acetone at 0C. is treated with one equivalent of phenylacetylchloride, with triethylamine being added to maintain pH at 6.5 to 7.5. When no further pH change is noted the reaction is worked up as in Example 23a to give the desired product. c. A suspension of the t-octyl amine salt (0.1 mol.) of the benzaldehyde Schiff base of 7-ADCA in ml of dimethoxyethane is treated with 10.8 g. of trimethyl silyl chloride at' 10C. for 2 hours. The reaction mix'is filtered and 0.1 eq. of sodium hydride as a mineral oil dispersion is added followed immediately by 28 g. of methyl iodide. After 2 to 3 hours, the reaction mix is diluted with 250 ml. H 0 and acidified to pH 2. After 20 minutes the result is filtered and the filtrate washed with ether. Adjusting the pH of the solution to 7 with triethylamine gives a solution of 7-methyl-7-ADCA which can be acylated with 0.10 mol. phenylacetyl chloride as in 23 to give the product.

d. By treatment of methyldesacetoxycephalosporanic acid, pmethoxybenzyl ester in benzene with 2.1 mmoles anisole and 3.5 mmoles trifluoroacetic acid for 6 hours. The desired product is extracted from the acid solution in good yield.

EXAMPLE 24 7-Amino-7-benzyldesacetoxycephalosporanic acid 7-Amino-7-benzyldesacetoxycephalosporanic acid is prepared by using benzyl chloride in lieu of methyl iodide of Example 14.

EXAMPLE 25 7-Benza1imino-7-benzyldesacetoxycephalosporanic acid, methyl ester 7-Benza1imino-7-benzyldesacetoxycephalosporanic acid, methyl ester is prepared by the procedure of Ex- 7-phenylacetamido-7- 7-Amino-7-benzyldesacetoxycephalosporanic acid, methylester is prepared by using the product of Example 25 to replace the substrate 7-methyl compound of Example 17.

EXAMPLE 27 7-Phenylacetamido-7-benzyldesacetoxycephalosporanic acid, methyl ester 7-Phehylacetamido-7-benzyldesacetoxycephalosporanic acid, methyl ester is prepared by using the product of Example 26 for the substrate in Example 21.

EXAMPLE 28 7-Phenylacetamido-7-benzyldesacetoxycephalosporanic acid 7-Phenylacetamid0-7-benzyldesacetoxycephalosporanic acid, is prepared by the Example 23 substituting the corresponding benzyl compound for the methyl compounds.

EXAMPLES 29-5l By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids:

a-(2-chlorophenoxy)propionic acid, a-(4-sulfamylphenoxy)-n-butyric acid, a-(3,4-dimethoxyphenoxy)-n-pentanoic acid, a-(3-methylphenoxy)isovaleric acid, oz-(4-methylthiophenoxy)propionic acid, a(4-dimethylaminophenoxy)-n-hexanoic acid, a-(Z-methoxyphenoxy)-n-decanoic acid, a-(2,4-dlchlorophenoxy)phenylacetic acid, a-(2-nitrophenoxy)-B-phenylpropionic acid, a-(Z-acetamidophenoxy )-7-phenylbutyric acid, a-(2,4-dimethylphenoxy)-n-butyric acid, a-(4-isopropylphenoxy)propionic acid, a-(3-bromophen0xy)-n-butyric acid, a-(2-iodophenoxy)phenylacetic acid, a-(Z-diethylaminophenoxy)isovaleric acid, a-(3,5-dichlorophenoxy)isohexanoic acid, a(4-cyclohexylphenoxy)propionic acid, a-phenoXy-isovaleric acid, a-phenoxy-n-decanoic acid, a-phenoxy-y-phenylbutyric acid, a-(2-benzylphenoxy)-n-butyric acid, a-(2-trifluoromethylphenoxy)propionic acid, and a-(4-fluorophenoxy)propionic acid, the products obtained are 7,-la-(2-chlorphenoxy)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-sulfamylphenoxy)-n-butyramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(3,4-dimethoxyphenoxy)-n-pentanoamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-m ethylphenoxy)isovaleramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-m ethylthiophenoxy)propionamido]-7- methyldesacetoxycephalosporanic acid,

10 7-[a-(4-dimemethylaminophenoxy)-nhexanoamido]-7-methyldesacetoxycephalosporanic acid, 7-[a-(2-methoxyphenoxy)-n-decanoamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(2,4-dichlorophen0xy)phenylacetamidol-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-nitrophenoxy)-B-phenylpropionamido]-7- methyldesacetoxycepthalosporanic acid, 7-[a-(Z-acetamidophenoxy)-y-phenylbutyramido]- 7-methyldesacetoxycephalosporanic acid, 7-[ a-(2,4-dimethylphenoxy)-n-butyramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-isopropylphenoxy)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-bromophenoxy)-n-butyramido ]-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-iodophenoxy)phenylacetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-diethylaminophenoxy)isovaleramidol-7- methyldesacetoxycephalosporanic acid, 7-[04-(3,5-dichlorophenoxy)isohexanoamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-cyclohexylphenoxy)propionamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-phenoxy-isovaleramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-phenoxy-n-decanoamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-phenoxy-y-phenylbutyramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-benzylphenoxy)-n butyramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-trifluoromethylphenoxy)propionamido1 -7- methyldesacetoxycephalosporanic acid, and 7-[a-(4-fluorophenoxy)propionamido]-7- methyldesacetoxycephalosporanic acid, respectively.

EXAM PLE S 52-8l By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids a-phenylthiopropionic acid,

a-paranitrophenylthiopropionic acid,

a-parachlorophenylthiopropionic acid, a-phenylthiobutyric acid, a-phenylthiocaproic acid, a-phenylthioisovaleric acid, a-(4-t-butylphenylthio)propionic acid, a-ortho-tolythiopropionic acid, a-ortho-nitrophenylthiopropionic acid, a-parachlorophenylthiobutyric acid, a-(3,4,5-trichlorophenylthio)propionic acid, a-(3-trifluoromethylphenylthio)butyric acid, wparabromophenylthioisovaleric acid, a-paraphenylphenylthiopropionic acid, a-(4-methoxyphenylthio)caproic acid, oz-(4-cyclohexylphenylthio)butyric acid, a-phenylthio-a-cyclohexylacetic acid, a-phenylthio-a-cyclopentylacetic acid, a-(2,4-dichlorophenylthio)caproic acid, a-(2,4-diisoamylphenylthio)propionic acid, a-(4-benzylphenylthio)propionic acid, a-(4-sulfamylphenylthio)butyric acid, a-(2-allyloxyphenylthio)propionic acid, a-(4-allylphenylthio)isovaleric acid,

1 l a-(4-dimethylaminophenylthio)propionic acid, a-(2,5-dichlorophenylthio)butyric acid, a-(2-iodophenylthio)propionic acid, a-(Z-acetamidophenylthio)propionic acid, a-(4-diethylaminophenylthio)propionic acid, and a-( 3-fluorophenylthio)butyric acid,

the products obtained are 7-(a-phenylthiopropionamido)-7- methyldesacetoxycephalosporanic acid, 7-( oz-paranitrophenylthiopropionamido )-7- methyldesacetoxycephalosporanic acid, 7-(a-parachlorophenylthiopropionamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-phenylthiobutyramido)-7- methyldesacetoxycephaiosporanic acid, 7-(a-phenylthiocaproamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-phenylthioisovaleramido)-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-t-butylphenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-ortho-tolylthiopropionamido1-7- methyldesacetoxycephalosporanic acid, 7-(a-ortho-nitrophenyithiopropionamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-parachlorophenylthiobutyramido )-7- methyldesacetoxycephaiosporanic acid, 7-[a-(3,4,5-trichlorophenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-trifluoromethylphenylthio)butyramid0]-7' methyldesacetoxycephaiosporanic acid, 7-(a-parabromophenylthioisovaleramido)-7- methyldesacetoxycephalosporanic acid, 7-(a-paraphenylphenylthiopropionamido)-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-methoxyphenylthio)caproamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-cyclohexylphenylthio)butyramidol-7- methyldesacetoxycephalosporanic acid, 7-(a-phenylthio-a-cyclohexylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-phenylthio-a-cyclopentylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-[a-(2,4-dichlorophenylthio)caproamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(2,4-diisoamylphenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-benzylphenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-sulfamylphenylthio)butyramido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(Z-allyloxyphenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-allylphenylthio)isovaleramido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-dimethylaminophenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(2,S-dichlorophenylthio)butyramido1-7- methyldesacetoxycephalosporanic acid, 7-[oz-(2-iodophenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-( Z-acetamidophenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-diethylaminophenylthio)propionamido1-7- methyldesacetoxycephalosporanic acid, and

12 7-[a-(3-fluorophenylthio)butyramid01-7- methyldesacetoxycephalosporanic acid, respectively.

EXAMPLES 82-95 By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids D,L-a-amino-( 3-thienyl)acetic acid,

a-amino-(5-ethyl-2-thienyl)acetic acid,

a-amino-(5-methyl-2-thienyl)acetic acid, a-amino-(5-t-butyl-2-thienyl)acetic acid, a-amino-(2,5-dimethyl-3-thienyl)acetic acid, a-amino-(5-chloro-2-thienyl)acetic acid, a-amino-(S-bromo-Z-thienyl)acetic acid, a-amino-(5-phenyl-3-chloro-2-thienyl)acetic acid, a-amino-(3,5-dimethyl-2-thienyl)acetic acid, a-amino-(S-cyclohexyl-Z-thienyl)acetic acid, a-amino-(5diethylamino-2-thienyl)acetic acid, a-amino-(4-methylsulfonyl-Z-thienyl)acetic acid, a-amino-(3-ethylthio-2-thienyl)acetic acid, and a-amin-(4-cycloheptyloxy-2-thienyl)acetic acid, the products obtained are D,L-7-[a-amino-(3-thienyl)acetamido]-7- methyldesacetoxycephalosporanic acid, 7-[aamino-(5-ethyl-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(S-methyl-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(5-t-butyl)-2-thienyl)acetamido-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(2,5-dimethyl-3-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino (5-chloro-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(5-bromo-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(5-phenyl-3-chl0ro-2- thienyl)acetamido]-7-methyldesace toxycephalosporanic acid, 7-[a-amino-(3,5-dimethyl-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[aamino-(S-cyclohexyl-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(5-diethylamino-2-thienyl)acetamido1- 7-methyldesacetoxycephalosporanic acid, 7-[oz-amino-(4-methylsulfonyl-Z-thienyl)acetamido]- 7-methyldesacetoxycephalosporanic acid, 7-[a-amino-(3-ethylthio-2-thienyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(4-cycloheptyloxy-2- thienyl)acetamido]-7methyldesacetoxycephaiosporanic acid, respectively.

EXAMPLES 96-118 By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride of the following carboxylic acids a-amino-p-chlorophenylacetic acid,

a-amino-p-methoxyphenylacetic acid, ailLiqghe mset c a ids oz-amino-4-diethylaminophenylacetic acid, a-amin0-4-trifluoromethylphenylacetic acid, a-amin0-2,4-dibromophenylacetic acid, a-amino-Z-nitrophenylacetic acid, a-amino-3-methylphenylacetic acid, a-amino-4-sulfamylphenylacetic acid,

13 a-amino-Z-iodophenylacetic acid, a-amino-4-t-butylphenylacetic acid, a-amino-2-acetamidophenylacetic acid, a-amino-3-nitrophenylacetic acid, a-amino-B,4-dimethoxyphenylacetic acid, a-amino-4-dimethylaminophenylacetic acid, a-amino-IZ,4-dichlorophenylacetic acid, a-amino-4-isopropylphenylacetic acid, a-amino-3-bromophenylacetic acid, a-amino-3-iodophenylacetic acid, a-amino-2-diethylaminophenylacetic acid, a-amino-Z-trifluoromethylphenylacetic acid, a-amino-4-fluorophenylacetic acid, and a-amino-3,4,5-trifluoromethylphenylacetic acid,

the products obtained are 7-(a-amino-p-chlorophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-p-methoxyphenylacetamido)-7- methyldesacetoxycephalosporanic acid, '9'fillliQQPllWfiliQfliEifiQ'?.

methyldesacetoxycephalosporanic acid, 7-(a-amino-4-diethylaminophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7( a-amino-4-trifluoromethylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2,4-dibromophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(wamino-2-nitrophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-3-methylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-4-sulfamylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2-iodophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-4-tbutylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2-acetamidophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-3-nitrophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-3,4-dimethoxyphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-4-dimethylaminophenylacetamido) -7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2,4-dichlorophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-4-isopropylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-B-bromophenyla cetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-3-iodophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2-diethylaminophenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-2-trifluor0methylphenylacetamido)-7- methyldesacetoxycephalosporanic acid, 7-(a-amino-4-fluorophenylacetamido)-7- methyldesacetoxycephalosporanic acid, and 7-(a-amino-3,4,5-trifluoromethylphenylacetamido)- 7 methyldesacetoxycephalosporanic acid, respectivley.

EXAMPLES 119-189 By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride:

benzyl chloride, 3,5-dinitrobenzoyl chloride, 2-chlorobenzoyl chloride, 2-methylbenzoyl chloride, 4-aminobenzoyl chloride, 4-nitrobenzoyl chloride, 4-hydroxybenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, 4-methylbenzoyl chloride, 4-chlorobenzoyl chloride, 3,4-dichlorobenzoyl chloride, 3-nitrobenzoyl chloride, 2,4,6-trimethoxybenzoyl chloride, 2-hydroxybenzoyl chloride, 4-ethoxybenzoyl chloride, 2,6-dimethoxybenzoyl chloride, 2,4,6-trimethylbenzoyl chloride, 2,6-dichlorobenzoyl chloride, 2,6-diethoxybenzoyl chloride, 2,6-di-n-butoxybenzoyl chloride, 2,6-dibenzyloxybenzoyl chloride, 2,3,6-trimethoxybenzoyl chloride, 2,4,6-tribromobenzoyl chloride, 2,6-di-n-propoxybenzoyl chloride, 2,6-dimethoxy-4-methylbenzoyl chloride, 4,6-diethyl-2-methoxybenzoyl chloride, 6-ethoxy-Z-methoxybenzoyl chloride, Z-methylthiobenzoyl chloride, 2-benzylthiobenzoyl chloride, Z-phenoxybenzoyl chloride, 2-phenylbenzoyl chloride, Z-methoxybenzoyl chloride, 4-sulfamylbenzoy1 chloride, 3,4-dim ethoxybenzoyl chloride, 4-methoxybenzoyl chloride, 3-methylbenzoyl chloride, 3-dimethylaminobenzoyl chloride, Z-methoxybenzoyl chloride, 2-chloro-3,4,5-trimethoxybenzoyl chloride, 2,4-dichlorobenzoyl chloride, 2-nitrobenzoyl chloride, 4-methylaminobenzoyl chloride, 2-acetamidobenzoyl chloride, 2,4-dimethylbenzoyl chloride, 2,4,5-trimethylbenzoyl chloride, 4-isopropylbenzoyl chloride, 3-bromobenzoyl chloride, 2-iodobenzoyl chloride, Z-ethylaminobenzoyl chloride, 2,5-dihydroxybenzoyl chloride, 4-hydroxy-3-methoxybenzoyl allylbenzoyl chloride, 4-allyloxybenzoyl chloride, 2-trifluoromethylbenzoyl chloride, 4-fluorobenzoyl chloride 2-phenylthiobenzoyl chloride, Z-benzylbenzoyl chloride, 2,6-dihydroxybenzoyl chloride, 2,6-diacetoxybenzoyl chloride, 2,6-dimethylthiobenzoyl chloride, 2,4,6-trinitrobenzoyl chloride, 2,6-diacetamidobenzoyl chloride, 2,6-dibromobenzoyl chloride, 2,6-dimethylbenzoyl chloride, 2,6-diethylbenzoyl chloride, 2,6-diisopropylbenzoyl chloride, 2,6-diallyloxybenzoyl chloride,

chloride, 4-

l 3-bromo2,6-dimethoxybenzoyl-chloride, 4-chloro-2,6-dimethoxybenzoyl chloride, 2-chloro-6-nitrobenzoyl chloride, and 2-hydroxy-6-methoxybenzoyl chloride, the products obtained are 7-(benzamido)-7-methyldesacetoxycephalosporanic acid, 7-(3,5-dinitrobenzamido)-lmethyldesacetoxycephalosporanic acid, 7-(2-chlorobenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2-methylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-amin0benzamido)-7-methyldesacetoxycephalosporanic acid, 7(4-nitrobenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-hydroxybenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(3,4,5-trimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4-methylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-chlorobenzamido)-7-methyldesacctoxycephalosporanic acid, 7-(3,4-dichlorobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-( 3-nitrobenzamido )-7-methyldesacetoxycephalosporanic acid, 7-(2,4,6-trimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-hydroxybenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-ethoxybenzamido)-7-mcthyldesacetoxycephalosporanic acid, 7-(2,6-dimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,4,6-trimethylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-dichlorobenzamido)-7- methyldesacetoxyccphalosporanic acid, 7-(2,6 diethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-di-n-butoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-dibenzyloxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,3,6-trimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,4,6-tribromobenzamid0)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-di-n-propoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-dimethoxy-4-methylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4,6-diethyl-2-methoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(-ethoxy-2-methoxybenzamido)-7- rnethyldesacetoxycephalosporanic acid, 7-(Z-methylthiobenzamido)-7- methyldesacetoxycephalosporanic acid,

7-(Z-benzylthiobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(Z-phenoxybenzamido)-Imethyldesacetoxycephalosporanic acid, 7-(2-phenylbenzamido)-7-methyldesacetoxycephalosporanic acid,

7-(Z-methoxybenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-sulfamylbenzamide)-7-methyldesacetoxycephalosporanic acid, 7-(3,4-dimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4-methoxybenzamido)-7'methyldesacetoxycephalosporanic acid, 7-(3-methylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(3-dimethylaminobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-methoxybenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2-chlore-3,4,5-trimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,4-dichlorobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-11itrobenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-methylaminobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-acetamidobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,4-dimethylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,4,5-trimethylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4-isopropylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(3-bromobenzamido)-7-methyldcsacetoxyccphalosporanic acid, 7-(2-iodobenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2-ethylaminobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,S-dihydroxybenzamido)-7- methyldesacetoxycephalosporanic acid,

' 7-(4-hydroxy-3-methoxybenzamido)-7 methyldesacetoxycephalosporanic acid, 7-(4-allylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(4-allyloxybenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2-trifluoromethylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4-fluorobenzamido )-7-methyldesacetoxycephalosporanic acid, 7-(2-phenylthiobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-benzylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2,6-dihydroxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-diacetoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-dimethylthiobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2.4,6-trinitrobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-diacetamidobenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-dibr0mobenzamido)-7- methyldesacetoxycephalosporanic acid,

' 7-(2,6-dimethylbenzamido)-7- methyldesacetoxycephalosporanic acid,

- l7 7-(2,6-diethylbenzamido)-7-methyldesacetoxycephalosporanic acid, 7-(2,6-diisopropylbenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2,6-diallyloxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(3-bromo-2,6-dimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(4-chloro-2,6-dimethoxybenzamido)-7- methyldesacetoxycephalosporanic acid, 7-(2-chloro6-nitrobenzamido)-7- methyldesacetoxycephalosporanic acid, and 7-(2-hydroxy 6-methoxybenzamido)-7- methyldesacetoxycephalosporanic acid, respectively.

EXAMPLES l90-200 By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride:

(4-nitrophenyl)acetyl chloride,

(4-bromophenyl)acetyl chloride,

(4-t-butylphenyl)acetyl chloride,

(4-trifluoromethylphenyl)acetyl chloride,

(3-fluorophenyl)acetyl chloride,

(4-sulfamylphenyl)acetyl chloride,

(2-benzylphenyl)acetyl chloride,

(3-methoxyphenyl)acetyl chloride,

(2iodophenyl)acetyl chloride,

(3-diethylaminophenyl)acetyl chloride, and

(2,4-diisoamylphenyl)acetyl chloride, the products obtained are 7-[a-(4-nitrophenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-bromophenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-t-butylphenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(4-trifluoromethylphenyl)acetamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-fluorophenyl)acetamido]-7 methyldesacetoxycephalosporanic acid, 7-[a-(4-sulfamylphenyl)acetamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-(Z-benzylphenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-methoxyphenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(2-iodophenyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-(3-diethylaminophenyl)acetamido]-7- methyldesacetoxycephalosporanic acid, and 7-[a-(2,4-diisoamylphenyl)acetamido]-7- methyldesacetoxycephal'osporanic acid, respectively.

EXAMPLES 201-248 By following the procedure of Example 23b and substituting an equivalent amount of the corresponding acid chloride:

3-m-chlorophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, l 3-(2,4-dichlorophenyl)-5 -methyl-4-isoiiazole-4- carbonyl chloride,

3-( 3 ,4-dichlorophenyl)-5 -methyl-4-isoXazole-4- carbonyl chloride, 3-p-tolyl-5-methyl-4-isoxazole-4-carbonyl chloride,

18 3-o-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-m-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-nitrophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-bromophenyl-5-methyl-4-isoxazole-4-carbonyl chloride, S-p-fluorophenyl-S-methyl-4-isoxazole-4i-carbonyl chloride. 3-p-methylsulfonylphenyl-S-methyl-4-isoxazole-4- carbonyl chloride, 3-p-methoxyphenyI-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-trifluoromethylphenylr5-methyl-4-isoxazole-4- carbonyl, chloride, 3-o-methoxyphenyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-p-ethoxyphenyl-5-methyl-4-isoxazole-4-carbonyI chloride, 3-(3,4-dimethoxyphenyl)-5-methyl-4-isoxazole-4- carbonyl chloride, 3-p-dimethylaminophenyl-5-methylr4-isoxazole-4- carbonyl chloride, 3-a-naphthyl-5-methyl-4-isoxazole-4-carbonyl chloride, 3-B-naphthyl-5-methyl-4-isoxazole-4-carbonyl chloride,

3-phenyl-5-ethyl-4-isoxazole-4-carbonyl chloride,

chlo- 3-methyl-5-p-tolyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-nitrophenyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5p-methoxyphenyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5-p-ethoxyphenyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5-(2,6-dimethoxyphenyl )-4-isoxazole-4- carbonyl chloride, 3-methyl-5-p-methylsulfonylphenyl-4-isoxazole-4 carbonyl chloride, 3-methyl-S-p-fluorophenyl-4-isoxozole-4-carbonyl chloride, 3-methyl-5-p-cyanophenyl-4-isoxazole-4-carbonyl chloride,

3-methyl-5-p-methylmercaptophenyl-4-isoxazole-4- carbonyl chloride, 3-methyl-5-p-climethylaminophenyl-4-isoxazole-4- carbonyl chloride, 3-methyl-S-a-naphthyl-4-isoxazole-4-carbonyl chloride,

21 7-[3-methyl-5-B-naphthyl-4- isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, 7-[ 3-ethyl-5-phenyl-4-isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, 7-[3-ethyl-5p-chlorophenyl-4- isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, 7-[3-isopropyl-5-phenyl-4- isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, 7-[3-tert. butyl-5-methyl-4- isoxazolylcarbonylamino[-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-fi-p-trifluoromethylphenyl-4- isoxazolylcarbonlyamino1-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-5-cyclohexyl-4- isoxazolylcarbonylamino]-7- methyldesacetoxycephalosporanic acid, 7-[3-cyclohexyl-5-methyl-4- isoxazolylcarbonylaminol-7- methyldesacetoxycephalosporanic acid, 7-[3-a-furyl-5-methyl-4-isoxazolylcarbonylaminol- 7-methyldesacetoxycephalosporanic acid, and

7-[3-a-thienyl-5-methyl-4- isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, tively.

respec- EXAMPLES 249-263 chloride, 3-(p-chlorophenyl)-5-methyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5-methylmercapto-4-isoxazole-4-carbonyl chloride, 5-(p-chlorophenyl)-3-methyl-4-isoxazole-4-carbonyl chloride, 3-methyl-5-(onitrophenyl)-4-isoxazole-4-carbonyl chloride, 5-isopropyl-3-methyl-4-isoxazole-4-carbonyl chloride, and 5-methyl-3-(p-chlorophenyl)-4-isoxazole-4-carbonyl chloride,

the products obtained are 7-[3,5-diphenyl-4isoxazolylcarbonylamincl-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-5-phenyl-4-isoxazolylcarbonylamino1-7- methyldesacetoxycephalosporanic acid, 7-[3,5-dimethyl-4-isoxazolylcarbonylamino]-7- methyldesac'etoxycephalsoporanic acid,

7-[5-benzyl-3-methyl-4-isoxazolylcarbonylamino]-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-5-styryl-4-isoxazolylcarbonylamino]-7- methyldesacetoxycephalosporanic acid, 7-[5-tert. butyl-3-phenyl-4- isoxazolylcarbonylamino]-7- methyldesacetoxycephalosporanic acid, 7-[5-(2-furyl)-3-methyl-4-isoxazolylcarbonylaminol- 7-methyldesacetoxycephalosporanic acid. 7-[3-methyl-5-(3,5'-dimethyl-4'-isoxazolyl)-4- isoxazolylcarbonylamido]-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-5-('2-thienyl)-4- isoxazolylcarbonylamido1-7- methyldesacetoxycephalosporanic acid, 7-[3-(p-chlorophenyl)-5-methyl-4- isoxazolylcarbonylamido]-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-S-methylmercapto-4- isoxazolylcarbonylamido]-7- methyldesacetoxycephalosporanic acid, 7-[5-(p-chlorophenyl)-3-methyl-4- isoxazolylcarbonylamido1-7- methyldesacetoxycephalosporanic acid, 7-[3-methyl-5-(o-nitrophenyl)-4- isoxazolylcarbonylamido1-7- methyldesacetoxycephalosporanic acid, 7-[5-isopropyl-3-methyl-4- isoxazolylcarbonylamido]-7- methyldesacetoxycephalosporanic acid, and 7-[5-methyl-3-(p-chlorophenyl)-4- isoxazolylcarbonylamido]- 7methyldesacetoxycephalosporanic acid, tively.

respec- EXAMPLE 264 To mL-aqueous solution (pH 8.0) of 10 g. crude 7-aminc-7-methyldesacetoxycephalosporanic acid are added 8 g. freshly distilled phenylacetaldehyde. After 2 hours agitation at room temperature, 250 ml. of methyl cyclohexanone are added and the pH adjusted to 4.0 with HCl. After 30 minutesthe phases are separated and the rich organic solvent is dried by azeotropic distillation of the water present. The triethylamine salt is prepared by the addition of 6.5 ml. of amine.

The solution is cooled to 0 5 and a mixture of 9.5 g. D(-)-2-phenylglycyl chloride hydrochloride in 100 ml. of methyl cyclohexanone is added over a period of 1 hour, maintaining a pH of 0 5C. After an additional hour agitation, 100 ml. cold phosphate buffer at pH 7.5 is added and the pH adjusted to 2.0. The solvent layer is discarded and the aqueous layer adjusted to pH 5.0. After 1 hour, filtration and drying yields 7-methylcephalexin.

By substituting the reaction product of sodium D(-)- a-aminophenyl acetate with methyl acetoacetate for 'the D()-2-phenylglycyl chloride hydrochloride in the foregoing procedure, 7-methyl-cephalexin is also produced.

EXAMPLES 265-274 In the procedure of Example 264 the D-( -2-' phenylglycyl chooride is replaced with an equimolar amount of a-( l-naphthyl)glycyl chloride, a-(2-napthyl)glycyl chloride, 7

1( I -chloro-2-napthyl)glycyl chloride, a-(2-methyl-7-naphthyl)glycyl chloride, a-(6-nitro-l-naphthyl)glycyl chloride, a-(2,7-dibromo-3-naphthyl)glycyl chloride, a-(4-trifluoromethyl-l-naphthyl)glycyl chloride, a-(8-iodo-l-naphthyl)glycyl chloride, a-( l-methoxy-2-naphthyl)glycyl chloride, and a-(4-acetamido-l-naphthyl)glycyl chloride, respectively, to produce 7-[a-amino-( l-napthyl )acetamido methyldesacetoxycephalosporanic acid, 7-[a-amino-(2-naphthyl)acetamido]7- methyldesacetoxycephalosporanic acid, 7-[a-amino-( 1-chloro-2-naphthyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(2-methyl-7-naphthyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[oz-amino-(6-nitrol -napthyl)acetamido]-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(2,7dibromo-3-naphthyl)acetamido1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-(4-trifluoromethyl-lnaphthyl)acetamido]-7-methyldesacetoxycephalosporanic acid, I 7-[a-amino( 8-iodo-l -naphthyl )acetamido 1-7- methyldesacetoxycephalosporanic acid, 7-[a-amino-( l-methoxy-Z-naphthyl )acetamidol-7- methyldesacetoxycephalosporanic acid, and 7-[a-amino-(4-acetamido-l-naphthyl)acetamido]-7- methyldesacetoxycephalosporanic acid, respectively.

EXAMPLE 275 10 .g. triethylamine salt of 7-amino-7- methyldesacetoxycephalosporanic acid is dissolved in 100 ml. methylene chloride. The solution is cooled to and 7 g. 2,6-dimethoxy benzoyl chloride is added dropwise over a period of 1% hours, maintaining the same temperature. After an additional 30 minutes, the solution is mixed with an equal volume of cold (5 phosphate buffer (pH 7.5). to complete the hydrolysis of the intermediate, the pH is adjusted to pH 2.0 and the mixture is agitated for minutes. The aqueous layer is discarded and the acid organic solvent layer is mixed with 50 ml. of cold water and neutralized to pH 7.5 with sodium hydroxide. The aqueous solution is separated and concentrated into 100 ml.

methyl isobutylketone. After standing overnight in the cold room, the crystals are filtered and dried to yield 7-methyl-7-(2,6- dimethoxybenzamido)desacetoxycephalosporanic acid.

EXAMPLE276-282 In the procedure of Example 275 the phenoxyacetyfi I respectively, to produce the sodium salt of respec- EXAMTEEzsa 7-Amino-7-allyldesacetoxycephalosporanic acid Following the procedure of Example 14 but utilizing allyl chloride in lieu of methyl chloride, the desireed product is recovered.

EXAMPLE 284 7-Amino-7-cyclohexyldesacetoxycephalosporanic acid Utilizing the procedure of Example 14 but substituting cyclohexyl chloride in lieu of methyl chloride, the desired porduct is recovered.

EXAMPLE 285 7-Benzalimino-7-allyldesacetoxycephalosporanic acid, methyl ester Following the procedure of Example l2'but utilizing an equivalent amount of allyl chloride in lieu of methyl iodide, the desired product is recovered.

EXAMPLE 286 7-Phenylacetamido-7-allyldesacetoxycepthalosporanic acid Utilixing the procedure of Example 230 but substituting allyl chloride for methyl iodide, the desired product is recovered.

- EXAMPLE 28 7 N-Benzylidene-7-aminocephalosporanic acid,

t-octylamine salt 15 grams 7 -aminocephalosporanic acid are slurried in 2 liters water and neutralized over a period of l to 1% hours with t-octylamine. The solution is clarified with 11.2 ml benzaldehyde over a period of one-half hour. After 2 hours stirring at room temperature, the solids are filtered off and washed with ml water. The product is dried at 40C.

i g EXAMPLE 288 7-Aminodesacetoxycephalosporanic acid, t-butyl ester 0.5 grams 7-aminodesacetoxycephalosporanic acid are dissolved in 15 ml dioxane in a pressure bottle and chilled in dry ice. Then-0.8 ml conc. sulphuric acid are i added along with 5 ml isobutylene. The mixture is stirred for 2 hours, at which time it is poured into an ice cold solution of 6 grams sodium bicarbonate in 100 ml water. This mixture is extracted with ethyl acetate several times. The organic extracts are dried over magnesium sulphate and evaporated to leave a solid product.

EXAMPLE 289 EXAMPLE 2% 7 Aminocephulospomnic acid unity ester 7-Phenylacetamido-7-methylcephalosporanic acid In lieu of the 7-amin0-7-methyldesacetoxycephalos- Followm procedure OfEXdmple 288 but Subs poranic acid, methyl ester utilized in Example 21 the wtlng 7'aminocepthalospomllic .acid for product of Example 293 is utilized. The desired prodammodesacetoxycephalosporamc acld the deslred uct is dissolved in trifluoroacetic acid for minutes at prOdUCt iS recovered 0C, then evaporated to yield the desired product, free acid.

EXAMPLE 290 What is claimed is:

. l0 N-Benzylidene-7-aminodesacetoxycephalosporanlc A compound havmg the formula acid, t-butyl ester 3 m moles 7-aminodesacetoxycephalosporanic acid, CH=N t-butyl ester are dissolved in 100 ml benzene and 20 m CH Y I V moles benzaldehyde are added along with a large ex- 5 0/ cess of magnesium sulphate. The reaction was stirred at room temperature for 22 hours at which time the magnesium sulfate is removed by filtration. The solvent was removed by evaporation in vacuo to leave a cryswherein R is lower alkyl; R is selected from the group consisting of hydrogen, lower alkyl, trichlotamne solid is selected from the group consisting of hydrogen, acetoxy, pyridinium and hydroxy; X is selected EXAMPLE 291 from the group consisting of hydrogen, hydroxy, N-Benzylidene-7-aminocephalosporanic acid, t-butyl g lower y lower y, nitrO n ester amino; and pharmaceutically accptable salts 25 thereof Following the procedure of Example 290 but substltuting 7-minocephalosporanic acid, t-butyl ester for 7- A compoun-d m accordance with claim 1 wherein aminodesacetox ce halos oranic acid t b t I este R ls methyl X ls hydrogen and Y Selected from the y p p u group consisting of hydrogen and acetoxy.

" EX'A 292 I 3. A compound in accordance with claim 2 having the name 7-benzahmmo-7-methyldesacetoxycephalos- 7Benzallmlno-7-methylcephalosporanlc acid, t-butyl poranic id pqnethoxybenzyl ester ester 4. A compound in accordance with claim 2 having Following the procedure of Example 12 but utilizing e name 7-benzaliminO-7-methylcephalosporanic N-benzyliclene-7-aminocephalosporanic acid, t-butyl acid, y esterester for 7-benzaliminodesacetoxycephalosporanic A Compound In accordance Wlth Claim 2 a ing acid, methyl ester the desired product is recovered. the name 749611121]lmino'7methyldesacetoxyceph3105' ,LWM poranic acid, methyl ester. 7

EXAMPLE 293 6. A compound in accordance with claim 2 having the name 7-benzalimino-7-methyldesacetoxycephalos- 40 poranic acid, benzyl ester.

7-Amino-7-methylcephalosporanic acid, t-butyl ester Utilizing the P 9FS EX? P l l flilyr 7. A compound in accordance with claim 2 having 2 iflg the Product Of EXample 292 for 7'benlalimino'7' the name 7-benzalimino-7-methyldesacetoxycephalosmethyldesacetoxycephalosporanic acid, methyl ester poranic acid benzhydryl esten the desired product is recovered. I a:

20 roethyl, benzyl, methoxybenzyl, and benzhydryl; Y

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. E 7 Dated r y 18, 1.975

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 2, line 24 "napthyl" should read naphthyl.

Col. 3, line 13 "asa" should read -as.

Col. 6, line 49, "Utilizing the" should read --A.

Col. 13 line 20, "aminophenyl-acetamido" should read -aminophenylacetamido-.

Col 16, line 3 "sulfamylbenzamide" should read --sulfamylbenzamido-.

Col l7 line 29, "2iodophenyl" should read --2iodophenyl--.

Col. 18, line 50, "5p" should read -5p--.

Col. 18, line 58 "isoxozole" should read --isoxazole--.

Col. 19, after line 2, the following should be inserted:

--3methyl-5B-naphthyl-4isoxazole4-carbonyl chloride,--.

Col. 19, line 32, a hyphen should be inserted between "4" and "isoxazolylcarbonylamino" Col 20, line 5, "isoxazolycarbonylamino" should read --isoxazolylcarbonylamino--.

Col. 20, line 21, "isoxazolylcarbonlamino" should read --isoxazolylcarbonylamino-.

Col. 20, line 42, "isoxazolycarbonylamino" should read --isoxazolylcarbonylamino-.

Col 20, line 54 "isoxazolycarbonylamino" should read -isoxazolylcarbonylamino-.

Col. 21, line 6, "5p" should read -5p-.

Col. 21, line 16, "isoxazolylcarbonlyamino" should read -isoxazolylcarbonylamino-.

Col. 21, line 45, 40' should read -4 Col. 22, line 33 a hyphen should be inserted between "7" and "methyldesacetoxycephalosporanic" 5,867, 79 February 18, 1975 Patent No. Dated Josenh Edward Dolfini e": Page Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Col. 24, line 21, "desireed" should read desired. Col. 24, line 42, "Utilixing" should read -Utilizing-. Col. 25, line 25, "7-minocephalosporanic" should read -7aminocephalosporanic.

eaned and sealed this let day of Jul 128;

SEA L Attest:

Ccamni sioner of Patents r" 4? Arresting; table's: and Trad k 

1. A COMPOUND HAVING THE FORMULA
 2. A compound in accordance with claim 1 wherein R3 is methyl, X is hydrogen and Y is selected from the group consisting of hydrogen and acetoxy.
 3. A compound in accordance with claim 2 having the name 7-benzalimino-7-methyldesacetoxycephalosporanic acid, p-methoxybenzyl ester.
 4. A compound in accordance with claim 2 having the name 7-benzalimino-7-methylcephalosporanic acid, t-butyl ester.
 5. A compound in accordance with claim 2 having the name 7-benzalimino-7methyldesacetoxycephalosporanic acid, methyl ester.
 6. A compound in accordance with claim 2 having the name 7-benzalimino-7-methyldesAcetoxycephalosporanic acid, benzyl ester.
 7. A compound in accordance with claim 2 having the name 7-benzalimino-7-methyldesacetoxycephalosporanic acid, benzhydryl ester. 